Study Pinpoints New Gene for Cystic Fibrosis

Dr. Christopher Karp, of the Cincinnati Children's Hospital Medical Center, and an international team of colleagues demonstrated that variants in a gene called IFRD1 can modulate the airway disease that marks cystic fibrosis (CF) by muting the pro-inflammatory activities of white blood cells called neutrophils.

Crucial in clearing bacterial infections, neutrophils have long been suspects in CF airway disease, Karp said. It was thought that they damage the airway via a hyperactive response to the persistent bacterial infections that plague people with CF.

"I think the significance of the paper is it further strengthens the importance of neutrophil function in modulating disease severity," said Chris Penland, director of research at the Cystic Fibrosis Foundation, which partially funded the study.

Though it's too early to recommend changes in genetic screening or counseling, the findings do implicate IFRD1 in particular, and neutrophil activation in general, as potential targets for drug development.

The results were published online Feb. 25 in Nature.

Researchers have long known that mutations in the gene CFTR were associated with cystic fibrosis, but were unable to account for the spectrum of lung disease severity that accompanies the disease.

That, Karp said, suggested two possibilities: "Either that there are strong environmental influences, and/or there are other genes that modify the expression of lung disease in cystic fibrosis."

A handful of modifiers had already been identified, all related to immune cell function. To identify additional candidates, Karp and his team scanned 100,000 genetic markers, called single nucleotide polymorphisms, across the genomes of two large cohorts of people with CF, looking for markers that segregated with airway disease severity. Of the six genetic variations that emerged, the most promising was IFRD1, which coincidentally is located relatively close to the CFTR gene.

IFRD1 is a transcription factor, a protein that regulates the expression of other genes. Karp said they found that the gene is highly expressed in neutrophils, and that neutrophils from mice that lack IFRD1 are less adept at carrying out their antibacterial activities, both in cultures and in animals. Yet at the same time, these mice also suffer less airway damage, weight loss and inflammation from those infections.

"Since we think in the CF airway that neutrophils are basically double-edged swords, and do help against infection but over time destroy the airway, it's a profoundly interesting phenotype," Karp said.

But that's in mice. Does IFRD1 status affect neutrophil function in humans, too?

Thus, the data suggest that subtle variations in the IFRD1 gene modulate neutrophil activity, which can in turn temper the degree of lung damage these cells cause in CF airways.

"This is an interesting finding that might explain why some CF patients have more severe lung deterioration than matched CF [patients] with the same [CFTR] genotype," said Dr. Robert Giusti, director of the Cystic Fibrosis Center at the Long Island College Hospital in Brooklyn, N.Y.

Giusti said the study could eventually pave the way to altered CF management.

"We might be able, by testing for the presence of these modifier genes, to alter our therapy and be more aggressive in the face of a lot of inflammation," he said. "And if we know that a patient is predisposed to inflammation, we can start early on with anti-inflammatory therapy and that might, therefore, limit the degree of lung disease."

However, Karp cautioned that the data do not yet support changing clinical practice.

"Until we get a better sense of what all the modifiers are and how they interact, the field is just not advanced enough," he said.

Researchers must first figure out how IFRD1 fits into the constellation of known and unknown CF gene modifiers and how it carries out its functions on a molecular level.

The study could drive new drug development, however, both at the level of IFRD1 itself and, more generally, at the level of neutrophil activity. In fact, Karp noted that the second most promising genetic location his team identified lies between two other genes also implicated in neutrophil development.

Though the data might not yet support a major drug development effort, Penland stressed that it is clear that people with CF need therapies that treat the underlying disease processes, not just provide symptom relief. "Therefore, what you would in the end have is patients who may die with CF rather than dying from CF," he said.

According to the Cystic Fibrosis Foundation, CF affects about 30,000 people in the United States and 70,000 worldwide.